Studies on Glucagon Receptor and
Antagonists of Glucagon Receptor for the Management of Diabetes Mellitus
Ghulam Abbas1,2*, Ahmed Al Harrasi2* and Hidayat Hussain2
1Department of Biological Sciences and Chemistry, University of Nizwa, Oman
2Chair of Oman’s Medicinal Plants and Marine Natural Products, University of Nizwa, Oman
Submission: January 16, 2018; Published: January 29, 2018
*Corresponding author: Ghulam Abbas, Department of Biological Sciences and Chemistry, University of Nizwa, Nizwa, Oman, Tel: +968-94354364; Fax: +968-25443400; Email: email@example.com
Ahmed Al Harrasi, Chair of Oman’s Medicinal Plants and Marine Natural Products, University of Nizwa, Nizwa, Oman, Email:firstname.lastname@example.org
How to cite this article: Ghulam A, Ahmed A H, Hidayat H. Studies on Glucagon Receptor and Antagonists of Glucagon Receptor for the Management
of Diabetes Mellitus. Curre Res Diabetes & Obes J. 2018; 5(4): 555667. DOI: 10.19080/CRDOJ.2018.05.555667.
Glucagon receptor plays an important role in the glucose homeostasis and thus is drug target for the management of hyperglycemia in type-2 diabetes mellitus. The suppression of glucagon secretion from the alpha-cells is the key to control hyperglycemic condition. The identification of non-peptide antagonists of glucagon receptor is an effective therapeutic approach to inhibit the glucagon secretion to achieve normal glucose index.
Diabetes mellitus is a chronic metabolic disorder which is spreading at an alarming rate all over the world. Glucagon receptor belongs to the G protein-coupled receptors (GPCRs) superfamily and an important drug target for type-2 diabetes . G-Proteins (guanine nucleotide binding proteins) actually act as molecular switches to turn on intracellular signaling as a result of GPCRs activation by intracellular stimuli. The GPCRs are also known as membrane bound receptors [2,3].
Both rat and mouse glucagon receptors are composed of 485-amino acids while the human glucagon receptor contains 477 amino acids (62kDa) and seven transmembrane (7TM) domain proteins . The human glucagon receptor is little shorter and about 80% identical to the mouse receptor. The structure-function studies revealed that all seven transmembrane helices are essential for the process of receptor folding and transporting to cell surface. Moreover, it is observed that the pattern of glycosylation may have a critical role in ligand recognition. Hence, for ligand binding, extracellular portion (intact N-terminal) of the receptor is required. It is found that carboxyl-terminal tail is not involved in the ligand binding
however it is necessary for desensitization and internalization [5-7].
Glucagon is a peptide hormone composed of 29-amino acids which is produced and secreted in the α-cells of the islets of langerhans in order to maintain normal glucose index by producing hepatic glucose to regulate insulin action . The amino acid sequence of glucagon peptide is shown in Figure 1.
Glucagon exerts its effects generally in the liver, where it stimulates the biological events such as glycogenolysis, gluconeogenesis, and ketogenesis to raise hepatic glucose output. Cyclic adenosine monophosphate (cAMP) actually
mediates most of the glucagon’s cellular effects. During this
process glucagon receptor binds with glucagon peptide to
activate adenylyl cyclase via its cognate heterotrimeric G protein
Gs to produce cAMP as shown in Figure 2 [4,6,8].
The production and release of large quantity of glucose from
the liver under the action of glucagon receptor is a major cause
of hyperglycemia in type- 2 diabetes. During type- 2 diabetes,
the level of glucagon is higher than both the insulin and blood
glucose levels. In this situation, one of the most effective
strategies for the treatment of hyperglycemia in type- 2 diabetes
involved development and discovery of new efficient therapeutic
agents (antagonists) to block the effect of glucagon on hepatic
glucose production . New therapies capable of maintaining
normal glucose index for longer period of time without serious
side effects are highly desirable . Non-peptide glucagon
antagonists of glucagon receptor are valuable because they are
orally useful active hypoglycemic agents as body can absorb
them properly [11,12].
In a study, a series of triarylimidazoles and triarylpyrroles was
investigated to discover new non-peptide, orally bioavailabile
antagonists of glucagons receptor. Compound 2-(4-Pyridyl)-
as shown in Figure 3, exhibited significant inhibition against
binding of isotopic labeled glucagon to the human glucagon
receptor with an IC50= 3.7±6 3.4nM .
Similarly, in another study, N-[3-cyano-6-(1,
1-dimethylpropyl)-4, 5, 6, 7-tetrahydro-1- enzothien-2-yl]-2-
ethylbutanamide (compound 2) exhibited potent GCGR antagonist
potential by inhibiting (IC50 of 181±10 nmol/l) the binding of
125I-glucagon to the membrane. Whereas, its structurally related
analog (compound 3) as shown in Figure 4, was a poor inhibitor
(20±1.5% inhibition at 10μmol/l) on glucagon binding assay
. The fungal bisanthroquinone skyrin was investigated for
its inhibitory potential against glucagon-stimulated production
of cAMP in vivo. Skyrin exhibited significant inhibition of cAMP
production from rat liver. The mechanism of antagonistic effect
of skyrin was non-competitive type for binding of glucagon to
its receptor instead it specifically uncoupled glucagon receptor
for adenylate cyclase activation. Skyrin and its oxygenated
derivative oxyskyrin are shown in Figure 5. Skyrin and oxyskyrin
inhibited glucagon stimulation of cAMP production with an EC50
=42μmol/L and EC50 =106μmol/L, respectively [14,15].